Abstract
apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.
Highlights
Abstract apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer’s disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR)
Particles ranging from 7 to 17 nm in diameter (Fig. 2B). These results demonstrate that both AZ-1 and AZ-2 increase ABCA1 expression and activity in CCF-STTG1 cells and elevate particles that resemble native lipidated apoE
We further explored the responses to compounds AZ-1 and AZ-2 in CNS cells, including primary human astrocytes, a human microglia cell line, human microglia clone 3 (HMC3), and primary human brain vascular pericytes
Summary
Abstract apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer’s disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Abstract apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer’s disease (AD). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. In AD mice, selective overexpression of ABCA1 increases CNS apoE lipidation and markedly decreases amyloid deposition [6]. Upregulation of ABCA1 through inhibition of microRNA-33 increases lipidation of apoE and decreases A levels in the brain [11]. Upregulating ABCA1 expression or function may be of therapeutic interest for AD by increasing apoE lipidation, thereby contributing to decreased A pathology
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